Apoptotic cell death and CPP32-like activation induced by thapsigargin and their prevention by nerve growth factor in PC12 cells.
Thapsigargin, an endoplasmic reticular Ca2+-ATPase inhibitor, induced apoptotic cell death (chromatin condensation and DNA fragmentation) accompanied by the activation of CPP32-like protease, a member of the interleukin-1beta converting enzyme protease (ICE) family, but not the activation of ICE-like protease. Nerve growth factor (NGF) completely inhibited the cell death and CPP32-like activation induced by thapsigargin while Ac-Asp-Glu-Val-Asp-CHO, an inhibitor of CPP32-like protease, reduced the cell death. PD98059, a specific inhibitor of Map kinase kinase, did not reduce the protective effect of NGF on thapsigargin-induced cell death. These results suggest that calcium ion-induced apoptotic cell death was mediated by CPP32-like, but not ICE-like, protease and was regulated by a neurotrophic factor possibly, through the Map kinase cascade independent pathway.
Takadera
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Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan. mhb01731@niftyserve.or.jp
Ohyashiki
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000032:analysis; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D020170:Caspase 1; D053148:Caspase 3; D020169:Caspases; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons; D009842:Oligopeptides / Q000494:pharmacology; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009414:Nerve Growth Factors; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D019284:Thapsigargin; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase; D020929:Mitogen-Activated Protein Kinase Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D000252:Calcium-Transporting ATPases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium